A process improvement method for preparing pinoxaden
By using inorganic alkali instead of organic alkali in the preparation process of zolinole ester, the process flow is simplified, the complex post-treatment and low yield problems caused by the use of triethylamine are solved, and efficient and low-cost product preparation is achieved. in industrial production.
Patent Information
- Application Number
- CN202210179138.7
- Authority / Receiving Office
- CN · China
- Patent Type
- Patents(China)
- Current Assignee / Owner
- Filing Date
- 2022-02-25
- Publication Date
- 2024-12-20
- Estimated Expiration
- 2042-02-25
AI Technical Summary
In the prior art, triethylamine is used as an acid binding agent in the preparation process of zolinole esters, resulting in complex post-treatment, high equipment investment cost, low product yield, and darker final product color requires further decolorization treatment.
The use of triethylamine is avoided, the process flow is simplified and the reaction is improved by performing deamination and acylation in organic solvents, and the addition of inorganic bases and halide salts in the intermediate treatment steps. Yield and product purity.
It realizes an efficient preparation of zolinoleate without triethylamine recovery, improves product purity and yield, simplifies process operations, reduces costs, and avoids decolorization. It is suitable for industrial production.
Smart Images
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Abstract
Description
Technical Field
[0001] The invention relates to the field of chemical synthesis, and in particular to an improved process for preparing pinoxaden. Background Art
[0002] Pinoxaden was developed by Syngenta and launched in 2006. It is a new phenylpyrazoline herbicide and also an acetyl-CoA carboxylase inhibitor herbicide. Pinoxaden is a selective, systemic post-emergence grass weed herbicide that can effectively control annual grass weeds in wheat and barley fields and is very suitable for spring cereals. It has good control effects on grass weeds such as wild oats, ryegrass, foxtail grass, hard grass, chrysanthemum, Japanese foxtail grass, and clover, especially for some vicious grass weeds such as wild oats, ryegrass, hard grass, and chrysanthemum. The control effect is close to 100%. It has the characteristics of high efficiency, broad spectrum, high safety, wide application period, and resistance to rain erosion. It degrades quickly in animals, plants, soil and the environment, does not stay, does not accumulate, and does not leach into groundwater. Compared with other wheat field herbicides, pinoxaden has huge development potential and market competitiveness.
[0003] The general synthesis method of pinoxaden is to synthesize the compound of formula III by deamination reaction of the compound of formula I and the compound of formula II, and then synthesize the compound of formula IV pinoxaden by reacting the compound of formula III with pivaloyl chloride under the action of a base (organic base), and the organic base generally used is triethylamine.
[0004]
[0005] Triethylamine is a colorless or light yellow transparent liquid, with a smelly ammonia smell, has the chemical property of a tertiary amine, is alkaline, and is highly irritating to skin and mucous membranes. Triethylamine is widely used as an acid binding agent (trapping agent for hydrogen chloride) in the acylation reaction of acyl chlorides, and the reaction generates a solid byproduct triethylamine hydrochloride, which is soluble in water, and aftertreatment adopts water extraction to obtain the waste water containing triethylamine hydrochloride. Triethylamine is more expensive and toxicity is higher, so the waste water containing triethylamine hydrochloride needs to be recovered by triethylamine.
[0006] Patent application CN106928253A discloses a method for preparing pinoxaden. The synthetic route is as follows: the compound of formula I is subjected to a deamination reaction with 1-oxa-4,5-diazepine (compound of formula II) hydrobromide to generate a compound of formula III, which is then subjected to an acylation reaction with pivaloyl chloride to generate pinoxaden. Triethylamine is used in both steps, and the total amount of triethylamine used is close to 7 equivalents (relative to the compound of formula I), and the two-step yields are 76.3% and 80%, respectively, and the total yield is only 61%.
[0007]
[0008] Patent CN1140528C discloses a method for preparing herbicide derivatives, wherein the preparation method of pinoxaden is a "one-pot method", wherein the compound of formula I, 1-oxa-4,5-diazepine hydrobromide and 4 equivalents of triethylamine are refluxed in xylene to generate the compound of formula III, and then reacted with pivaloyl chloride after cooling to generate pinoxaden. Although the method has simple steps, triethylamine is also used, and the total yield is 62%.
[0009] Patent CN112028906B discloses a "one-pot method" for preparing pinoxaden, which is similar to the method of patent CN1140528C. A catalyst is added and the amount of triethylamine is reduced to 2 equivalents. However, the highest yield is only 72%, and the recovery of triethylamine is still a difficulty that needs to be solved in the process.
[0010] In summary, triethylamine is generally used as acid binding agent in the prior art, but the post-processing of triethylamine is very complicated, and it is necessary to be equipped with a special triethylamine recovery device, which undoubtedly increases the investment cost of equipment and the complexity of process, and the yield of pinoxaden has not yet reached a higher level. In addition, organic bases such as triethylamine are used to prepare pinoxaden, and the final product color is darker, and further decolorization treatment is often required. Therefore, it is urgent to develop a process for preparing pinoxaden without using triethylamine, reaction yield and product purity. Summary of the invention
[0011] Problem that the invention aims to solve
[0012] In order to avoid the use of triethylamine and to improve the reaction yield and product purity, the present invention provides an improved process for preparing pinoxaden.
[0013] Solutions for solving problems
[0014] The present invention provides an improved process for preparing pinoxaden, which comprises the following steps:
[0015]
[0016] (1) Deamination reaction: reacting the compound of formula I with the compound of formula II in the presence of an organic solvent A that is immiscible with water to obtain a solution containing the compound of formula III;
[0017] (2) an intermediate treatment step: contacting the solution containing the compound of formula III obtained in step (1) with an aqueous solution of an inorganic base to obtain a two-phase mixture;
[0018] (3) Acylation reaction: react the two-phase mixture obtained in step (2) with pivaloyl chloride under sufficient mixing, and obtain pinoxaden after post-treatment.
[0019] Preferably, the inorganic base in step (2) is sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate or lithium carbonate.
[0020] More preferably, the inorganic base in step (2) is sodium hydroxide or potassium hydroxide.
[0021] Preferably, in step (2), a halide salt is added to the two-phase mixture.
[0022] Preferably, the halide salt is sodium chloride, potassium chloride, lithium chloride, sodium bromide, potassium bromide or lithium bromide.
[0023] More preferably, the halide salt is sodium chloride or potassium chloride.
[0024] Preferably, the water-immiscible organic solvent A in step (1) is chlorobenzene, xylene or dichlorobenzene.
[0025] More preferably, the water-immiscible organic solvent A in step (1) is chlorobenzene.
[0026] Preferably, the mass concentration of alkali metal ions in the aqueous phase of the two-phase mixture in step (2) is 7%-30%.
[0027] In a preferred embodiment, in step (2), the solution containing the compound of formula III obtained in step (1) is contacted with an aqueous solution of an inorganic base, extracted and separated, and the aqueous phase is contacted with an organic solvent B that is immiscible with water to obtain a two-phase mixture.
[0028] Preferably, the water-immiscible organic solvent B in step (2) is 1,2-dichloroethane, dichloromethane, ethyl acetate or sec-butyl acetate.
[0029] More preferably, the water-immiscible organic solvent B in step (2) is 1,2-dichloroethane or ethyl acetate.
[0030] Further preferably, the water-immiscible organic solvent B in step (2) is 1,2-dichloroethane.
[0031] Preferably, the mass concentration of alkali metal ions in the aqueous phase of the two-phase mixture in step (2) in the above preferred embodiment is 2%-30%.
[0032] Preferably, a phase transfer catalyst is added to the two-phase mixture in step (2) above.
[0033] Preferably, the phase transfer catalyst is a quaternary ammonium salt or a crown ether.
[0034] More preferably, the phase transfer catalyst is tetrabutylammonium chloride, tetramethylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium hydrogen sulfate or benzyltriethylammonium chloride.
[0035] Further preferably, the phase transfer catalyst is tetrabutylammonium chloride or tetramethylammonium chloride.
[0036] Preferably, the molar ratio of the phase transfer catalyst to the compound of formula I is 0.001-0.02:1.
[0037] More preferably, the molar ratio of the phase transfer catalyst to the compound of formula I is 0.01:1.
[0038] In a preferred embodiment, in step (2), before the solution containing the compound of formula III obtained in step (1) is contacted with an aqueous solution of an inorganic base, the solution containing the compound of formula III is first contacted with an aqueous solution of an acid, extracted and separated, and then the organic phase is contacted with the aqueous solution of the inorganic base.
[0039] Preferably, the acid in step (2) is an inorganic acid or an organic acid.
[0040] More preferably, the acid in step (2) is hydrochloric acid, sulfuric acid or acetic acid.
[0041] More preferably, the acid in step (2) is hydrochloric acid.
[0042] Preferably, the mass concentration of the aqueous solution of the acid in step (2) is 2wt%-20wt%.
[0043] More preferably, the mass concentration of the aqueous solution of the acid in step (2) is 10 wt %.
[0044] Preferably, the molar ratio of the acid to the compound of formula I in step (2) is 0.2-5:1.
[0045] More preferably, the molar ratio of the acid to the compound of formula I in step (2) is 2:1.
[0046] Preferably, the molar ratio of the compound of formula II to the compound of formula I in step (1) is 1-5:1.
[0047] More preferably, the molar ratio of the compound of formula II to the compound of formula I in step (1) is 1:1.
[0048] Preferably, the mass ratio of the water-immiscible organic solvent A to the compound of formula I in step (1) is 1-10:1.
[0049] More preferably, the mass ratio of the water-immiscible organic solvent A to the compound of formula I in step (1) is 3-4:1.
[0050] Preferably, the reaction temperature in step (1) is 100°C-140°C.
[0051] Preferably, the reaction time in step (1) is the time required for the purity of the compound of formula III in the solution containing the compound of formula III to reach at least 90%.
[0052] More preferably, the reaction time in step (1) is the time required for the purity of the compound of formula III in the solution containing the compound of formula III to reach at least 96%.
[0053] Further preferably, the reaction time in step (1) is the time required for the purity of the compound of formula III in the solution containing the compound of formula III to reach at least 98%.
[0054] Preferably, the temperature is lowered after the reaction in step (1) is completed.
[0055] Preferably, the cooling temperature is 20°C-100°C.
[0056] Preferably, the mass concentration of the aqueous solution of the inorganic base in step (2) is 1wt%-50wt%.
[0057] More preferably, the mass concentration of the aqueous solution of the inorganic base in step (2) is 3wt%-40wt%.
[0058] Further preferably, the mass concentration of the aqueous solution of the inorganic base in step (2) is 3wt%-30wt%.
[0059] Preferably, the molar ratio of the inorganic base to the compound of formula I in step (2) is 1-3:1.
[0060] More preferably, the molar ratio of the inorganic base to the compound of formula I in step (2) is 1.2-2:1.
[0061] Preferably, the mass ratio of the water-immiscible organic solvent B to the compound of formula I in step (2) is 1-10:1.
[0062] More preferably, the mass ratio of the water-immiscible organic solvent B to the compound of formula I in step (2) is 3-5:1.
[0063] Preferably, the molar ratio of pivaloyl chloride to the compound of formula I in step (3) is 1-3:1.
[0064] More preferably, the molar ratio of pivaloyl chloride to the compound of formula I in step (3) is 1:1.
[0065] Preferably, the temperature is controlled during the reaction in step (3).
[0066] Preferably, the temperature of the temperature control in step (3) is 0°C-25°C.
[0067] More preferably, the temperature of the temperature control in step (3) is 0°C-20°C.
[0068] Further preferably, the temperature of the temperature control in step (3) is 0°C-10°C.
[0069] Preferably, the reaction time in step (3) is the time required for the compound of formula III to react completely.
[0070] Preferably, the post-treatment in step (3) is as follows: after the reaction is completed, the phases are separated, the organic phase is washed with water, concentrated, and crystallized to obtain pinoxaden.
[0071] Preferably, the crystallization solvent in step (3) is n-hexane, cyclohexane, methylcyclohexane, n-heptane, n-octane or petroleum ether.
[0072] More preferably, the crystallization solvent in step (3) is n-hexane.
[0073] Preferably, the mass ratio of the crystallization solvent to the compound of formula I is 1-10:1.
[0074] More preferably, the mass ratio of the crystallization solvent to the compound of formula I is 3-5:1.
[0075] Effects of the Invention
[0076] The process improvement method for preparing pinoxaden provided by the present invention changes the acid binding agent in the prior art from an organic base to an inorganic base, avoids the use of triethylamine, reduces the recovery process, is convenient for continuous industrial production, and also satisfies the color state of the product, avoids the decolorization process. The process method includes a two-step reaction of deamination and acylation, and an intermediate treatment step, but there is no need for a separation and purification step after the deamination reaction, and the intermediate treatment step is simple to operate, and does not increase complex operation procedures. Compared with the prior art, the process method greatly improves reaction yield and product purity, and is simple to operate, reduces filtering processes, does not use special reagents, has low cost, is green and environmentally friendly, and is suitable for industrialized amplification production. DETAILED DESCRIPTION
[0077] Definition of terms
[0078] The "acid-binding agent" in the present invention refers to a reagent that captures hydrogen ions in the acylation reaction to accelerate the rate of the acylation reaction and prevent the generation of by-products, and is usually an alkaline reagent.
[0079] The "phase transfer catalyst" in the present invention refers to a type of catalyst that can help reactants transfer from one phase to another phase where the reaction can occur, thereby accelerating the reaction rate of the heterogeneous system, overcoming the shortcomings of slow heterogeneous organic reaction rate, low yield, incomplete reaction, etc. The commonly used phase transfer catalysts in organic synthesis are quaternary ammonium salts, such as tetrabutylammonium bromide, tetrabutylammonium chloride, tetrabutylammonium hydrogen sulfate, tetramethylammonium chloride and benzyltriethylammonium chloride.
[0080] The "purity" in the present invention refers to the HPLC purity measured by the peak area normalization method.
[0081] The "equivalent" in the present invention refers to the amount of the reagent used in the reaction, specifically the molar ratio of the reagent to the compound of formula I, abbreviated as "eq".
[0082] The abbreviations in the context of the present invention have the following meanings:
[0083] abbreviation meaning eq equivalent DCE 1,2-Dichloroethane DCM Dichloromethane HPLC High performance liquid chromatography
[0084] Synthesis process
[0085] In the existing synthesis process of pinoxaden, triethylamine is generally used as an acid binding agent. The post-treatment of triethylamine is very complicated, and the yield of pinoxaden is also low. In addition, the use of organic bases such as triethylamine to prepare pinoxaden results in a darker color of the final product, which often requires further decolorization. In order to solve the above problems, the inventors tried to use inorganic bases as acid binding agents. After a large number of experimental studies, various process parameters were optimized, and finally the reaction yield and product purity were improved without using organic bases. Specific synthesis steps:
[0086]
[0087] (1) Deamination reaction: reacting the compound of formula I with the compound of formula II in the presence of an organic solvent A that is immiscible with water to obtain a solution containing the compound of formula III;
[0088] (2) an intermediate treatment step: contacting the solution containing the compound of formula III obtained in step (1) with an aqueous solution of an inorganic base to obtain a two-phase mixture;
[0089] (3) Acylation reaction: react the two-phase mixture obtained in step (2) with pivaloyl chloride under sufficient mixing, and obtain pinoxaden after post-treatment.
[0090] In one embodiment, the inorganic base in step (2) is sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate or lithium carbonate.
[0091] In a preferred embodiment, the inorganic base in step (2) is sodium hydroxide or potassium hydroxide.
[0092] In one embodiment, in step (2), a halide salt is added to the two-phase mixture.
[0093] In one embodiment, the halide salt is sodium chloride, potassium chloride, lithium chloride, sodium bromide, potassium bromide, or lithium bromide.
[0094] In a preferred embodiment, the halide salt is sodium chloride or potassium chloride.
[0095] In one embodiment, the water-immiscible organic solvent A in step (1) is chlorobenzene, xylene or dichlorobenzene.
[0096] In a preferred embodiment, the water-immiscible organic solvent A in step (1) is chlorobenzene.
[0097] In one embodiment, the mass concentration of alkali metal ions in the aqueous phase of the two-phase mixture in step (2) is 7%-30%.
[0098] In one embodiment, in step (2), the solution containing the compound of formula III obtained in step (1) is contacted with an aqueous solution of an inorganic base, extracted and separated, and the aqueous phase is contacted with an organic solvent B that is immiscible with water to obtain a two-phase mixture.
[0099] In one embodiment, the water-immiscible organic solvent B in step (2) is 1,2-dichloroethane, dichloromethane, ethyl acetate or sec-butyl acetate.
[0100] In a preferred embodiment, the water-immiscible organic solvent B in step (2) is 1,2-dichloroethane or ethyl acetate.
[0101] In a more preferred embodiment, the water-immiscible organic solvent B in step (2) is 1,2-dichloroethane.
[0102] In the above embodiment, the mass concentration of alkali metal ions in the aqueous phase of the two-phase mixture in step (2) is 2%-30%.
[0103] In one embodiment, a phase transfer catalyst is added to the two-phase mixture in step (2) above.
[0104] In one embodiment, the phase transfer catalyst is a quaternary ammonium salt or a crown ether.
[0105] In a preferred embodiment, the phase transfer catalyst is tetrabutylammonium chloride, tetramethylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium hydrogen sulfate or benzyltriethylammonium chloride.
[0106] In a more preferred embodiment, the phase transfer catalyst is tetrabutylammonium chloride or tetramethylammonium chloride.
[0107] In one embodiment, the molar ratio of the phase transfer catalyst to the compound of formula I is 0.001-0.02:1.
[0108] In a preferred embodiment, the molar ratio of the phase transfer catalyst to the compound of formula I is 0.01:1.
[0109] In one embodiment, in step (2), before the solution containing the compound of formula III obtained in step (1) is contacted with an aqueous solution of an inorganic base, the solution containing the compound of formula III is first contacted with an aqueous solution of an acid, and then the organic phase is contacted with the aqueous solution of the inorganic base. The addition of an aqueous solution of an acid for extraction and separation can remove the compound of formula II remaining in the reaction and the black tar produced by the reaction, thereby improving the product quality.
[0110] In one embodiment, the acid in step (2) is an inorganic acid or an organic acid.
[0111] In a preferred embodiment, the acid in step (2) is hydrochloric acid, sulfuric acid or acetic acid.
[0112] In a more preferred embodiment, the acid in step (2) is hydrochloric acid.
[0113] In one embodiment, the mass concentration of the aqueous solution of the acid in step (2) is 2 wt%-20 wt%.
[0114] In a preferred embodiment, the mass concentration of the aqueous solution of the acid in step (2) is 10 wt%.
[0115] In one embodiment, the molar ratio of the acid to the compound of formula I in step (2) is 0.2-5:1.
[0116] In a preferred embodiment, the molar ratio of the acid to the compound of formula I in step (2) is 2:1.
[0117] In one embodiment, the molar ratio of the compound of formula II to the compound of formula I in step (1) is 1-5:1.
[0118] In a preferred embodiment, the molar ratio of the compound of formula II to the compound of formula I in step (1) is 1:1.
[0119] In one embodiment, the mass ratio of the water-immiscible organic solvent A to the compound of formula I in step (1) is 1-10:1.
[0120] In a preferred embodiment, the mass ratio of the water-immiscible organic solvent A to the compound of formula I in step (1) is 3-4:1.
[0121] In one embodiment, the temperature of the reaction in step (1) is 100°C-140°C.
[0122] In one embodiment, the reaction time in step (1) is the time required to make the purity of the compound of formula III in the solution containing the compound of formula III reach at least 90%.
[0123] In a preferred embodiment, the reaction time in step (1) is the time required for the purity of the compound of formula III in the solution containing the compound of formula III to reach at least 96%.
[0124] In a more preferred embodiment, the reaction time in step (1) is the time required for the purity of the compound of formula III in the solution containing the compound of formula III to reach at least 98%.
[0125] In one embodiment, the temperature is lowered after the reaction in step (1) is completed.
[0126] In one embodiment, the cooling temperature is 20°C-100°C.
[0127] In one embodiment, the aqueous solution of the inorganic base in step (2) has a mass concentration of 1 wt% to 50 wt%.
[0128] In a preferred embodiment, the mass concentration of the aqueous solution of the inorganic base in step (2) is 3wt%-40wt%.
[0129] In a more preferred embodiment, the aqueous solution of the inorganic base in step (2) has a mass concentration of 3 wt% to 30 wt%.
[0130] In one embodiment, the molar ratio of the inorganic base to the compound of formula I in step (2) is 1-3:1.
[0131] In a preferred embodiment, the molar ratio of the inorganic base to the compound of formula I in step (2) is 1.2-2:1.
[0132] In one embodiment, the mass ratio of the water-immiscible organic solvent B to the compound of formula I in step (2) is 1-10:1.
[0133] In a preferred embodiment, the mass ratio of the water-immiscible organic solvent B to the compound of formula I in step (2) is 3-5:1.
[0134] In one embodiment, the molar ratio of pivaloyl chloride to the compound of formula I in step (3) is 1-3:1.
[0135] In a preferred embodiment, the molar ratio of pivaloyl chloride to the compound of formula I in step (3) is 1:1.
[0136] In one embodiment, the temperature is controlled during the reaction in step (3).
[0137] In one embodiment, the temperature of the temperature control in step (3) is 0°C-25°C.
[0138] In a preferred embodiment, the temperature of the temperature control in step (3) is 0°C-20°C.
[0139] In a more preferred embodiment, the temperature of the temperature control in step (3) is 0°C-10°C.
[0140] In one embodiment, the reaction time in step (3) is the time required to completely react the compound of formula III.
[0141] In one embodiment, the post-treatment in step (3) is as follows: after the reaction is completed, the phases are separated, the organic phase is washed with water, concentrated, and crystallized to obtain pinoxaden.
[0142] In one embodiment, the crystallization solvent in step (3) is n-hexane, cyclohexane, methylcyclohexane, n-heptane, n-octane or petroleum ether.
[0143] In a preferred embodiment, the crystallization solvent in step (3) is n-hexane.
[0144] In one embodiment, the mass ratio of the crystallization solvent to the compound of formula I is 1-10:1.
[0145] In a preferred embodiment, the mass ratio of the crystallization solvent to the compound of formula I is 3-5:1.
[0146] The technical scheme of the present invention is further described below in conjunction with the examples. It should be understood that the following examples are only used to explain and illustrate the present invention, and are not intended to limit the scope of protection of the present invention. Unless otherwise specified, the instruments, materials and reagents used in the following examples can all be obtained by conventional commercial means.
[0147] Example
[0148] Example 1
[0149] Weigh the compound of formula II (9.8 g, 0.096 mol), the compound of formula I (23.8 g, 0.096 mol) and chlorobenzene (80 g) into a 250 mL three-necked flask, start heating, maintain the reaction temperature at 126° C., stir the reaction for 5 h, stop the reaction, and the relative content is 98% by HPLC. Cool to room temperature (25° C.), add 10 wt % aqueous sodium hydroxide solution (46.08 g, 0.1152 mol), extract and separate the phases, collect the aqueous phase, add the organic solvent DCE (96 g) to the aqueous phase, slowly add pivaloyl chloride (11.52 g, 0.096 mol) dropwise, maintain the internal temperature at 10° C., stir for 10 min, take the organic phase for analysis, take a sample for analysis, and the relative content by HPLC is 92%, indicating that the raw material reaction is complete. The phases were allowed to stand and separated, the organic phase was collected, washed with 50 g of water, separated, concentrated to remove DCE, n-hexane (100 g) was added for crystallization, and the product was filtered to obtain the product (the product HPLC purity was 99%, the total yield based on the compound of formula II was 92.5%, and the product color was yellowish).
[0150] Example 2
[0151] Weigh the compound of formula II (9.8 g, 0.096 moL), the compound of formula I (23.8 g, 0.096 mol) and chlorobenzene (80 g) into a 250 mL three-necked flask, start heating, keep the reaction temperature at 126° C., stir for 5 h, stop the reaction, the relative content is 98% by HPLC, cool to room temperature (25° C.), add 10 wt % aqueous hydrochloric acid solution (70 g, 0.192 mol) for extraction, separate the phases, collect the organic phase, add 10 wt % aqueous sodium hydroxide solution (46.08 g, 0.1152 mol) to the organic phase for extraction, separate the phases, collect the aqueous phase, add organic solvent DCE (96 g) to the aqueous phase, slowly add pivaloyl chloride (11.52 g, 0.096 mol) dropwise, maintain the internal temperature at 10° C., stir for 10 min, take samples for analysis, and the relative content is 98% by HPLC, indicating that the raw materials are completely reacted. The organic phase was collected by phase separation, washed with 50 g of water, concentrated to remove DCE, added with n-hexane (100 g) for crystallization, and filtered to obtain the product (HPLC purity of the product was 99%, the total yield based on the compound of formula II was 95%, and the product was white).
[0152] Example 3-15
[0153] According to the method of Example 2, the concentration or amount of sodium hydroxide aqueous solution, the type of organic solvent added, the temperature of the acylation reaction, and the addition of the catalyst were adjusted, and the experimental results are shown in Table 1. Wherein, "NaOH dosage" is the equivalent calculated based on the equivalent of the compound of formula I; "conversion rate" refers to the ratio of the reacted compound of formula III to the raw material of the compound of formula III, which is used to indicate the degree of reaction; "HPLC relative content" refers to the HPLC purity of pinoxaden in the reaction solution after the reaction is completed calculated according to area normalization; total yield refers to the product yield based on the compound of formula II.
[0154] Table 1
[0155]
[0156] Conclusion: As shown in Table 1, the reaction can be carried out when the organic solvent is DCE, toluene, o-xylene, dichloropropane, tetrachloroethylene, ethyl acetate, sec-butyl acetate and DCM. When DCE, DCM, ethyl acetate and sec-butyl acetate are selected, the total reaction yield is higher, which can reach more than 90%; when the mass concentration of the sodium hydroxide solution is low (5wt%), that is, when the sodium ion concentration is 2.9%, the reaction effect is also better; the acylation reaction temperature is preferably controlled at 0°C-10°C; from the comparison of Example 10 and Example 12, it can be seen that the addition of a phase transfer catalyst can further improve the reaction yield.
[0157] Example 16
[0158] Weigh the compound of formula II (9.8 g, 0.096 moL), the compound of formula I (23.8 g, 0.096 mol) and chlorobenzene (80 g) into a 250 mL three-necked flask, start heating, keep the reaction temperature at 126 ° C, stir for 5 hours, stop the reaction, HPLC detection relative content is 98%, cool to room temperature (25 ° C), add 10 wt % hydrochloric acid aqueous solution (70 g, 0.192 mol) for extraction, phase separation, collect the organic phase, add 20 wt % sodium hydroxide aqueous solution (23 g, 0.1152 mol) to the organic phase at one time, add phase transfer catalyst tetrabutylammonium chloride (0.2668 g, 0.00096 mol), cool to 0 ° C, slowly add pivaloyl chloride (11.52 g, 0.096 mol), after the addition is complete, stir for 10 minutes, take samples for analysis, and the sampling analysis and detection HPLC relative content is 98%, and the raw material reaction is complete. The organic phase was collected by phase separation, washed with water, concentrated to remove the organic solvent chlorobenzene, added with n-hexane (100 g) for crystallization, and filtered to obtain the product (the product HPLC purity was 98.5%, the total yield based on the compound of formula II was 95%, and the product was white).
[0159] Examples 17-22
[0160] According to the method of Example 16, the concentration of the sodium hydroxide aqueous solution and the conditions of the acylation reaction (including temperature and catalyst) were adjusted. The experimental results are shown in Table 2.
[0161] Table 2
[0162]
[0163] Remark:
[0164] (1)Na + The mass concentration is obtained by calculation, and the specific calculation method is as follows:
[0165]
[0166] (2) OH - The mass concentration is obtained by calculation, and the specific calculation method is as follows:
[0167]
[0168] Conclusion: By comparing Example 17 with Example 18, and Example 20 with Example 16, it can be seen that increasing the mass concentration of NaOH solution (Na + The mass concentration increases accordingly) can significantly improve the reaction conversion rate and total yield; the acylation reaction temperature control at 0℃-20℃ has a good effect, the lower the temperature, the higher the yield.
[0169] Embodiment 23
[0170] The intermediate of the compound of formula II (9.8 g, 0.096 mol), the intermediate of the compound of formula I (23.8 g, 0.096 mol) and chlorobenzene (80 g) were weighed and added into a 250 mL three-necked flask, and heating was started, and the reaction temperature was maintained at 126 ° C. After stirring for 5 h, the reaction was stopped. The relative content was 98% by HPLC. The temperature was cooled to room temperature (25 ° C), and 10 wt% hydrochloric acid aqueous solution (70 g, 0.192 mol) was added for extraction. The phases were separated, and the organic phase was collected and the organic phase was added to the organic phase. 10wt% sodium hydroxide aqueous solution (46.08g, 0.1152mol) was added at one time, and then tetrabutylammonium chloride (0.2668g, 0.00096mol) and sodium chloride solid (6.73g, 0.1152mol) were added as phase transfer catalyst, and the temperature was lowered to 0°C, and pivaloyl chloride (11.52g, 0.096mol) was slowly added dropwise. After the addition was complete, the mixture was stirred for 10min, and the relative content of HPLC was 97% after sampling and analysis. The raw material reaction was complete. The organic phase was collected by phase separation, washed with water, concentrated to remove the organic solvent chlorobenzene, and n-hexane (100g) was added for crystallization, and the product was filtered to obtain the product (the product HPLC purity was 99%, and the total yield based on the compound of formula II was 93%, and the product was white).
[0171] Examples 24-25
[0172] According to the method of Example 23, the concentration of the sodium hydroxide aqueous solution and the conditions of the acylation reaction (including temperature and amount of sodium chloride) were adjusted. The experimental results are shown in Table 3.
[0173] Table 3
[0174]
[0175] Remark:
[0176] (1)Na + The mass concentration is calculated. The added sodium chloride is calculated based on the amount of sodium chloride entering the aqueous phase NaOH solution. The specific calculation method is as follows:
[0177]
[0178] (2) OH - The mass concentration is obtained by calculation, and the specific calculation method is as follows:
[0179]
[0180] Conclusion: By comparing Example 23 with Example 20, it can be seen that under the same conditions of NaOH concentration and dosage, the addition of NaCl can significantly improve the conversion rate and total yield of the reaction; + The mass concentration has a great influence on the reaction. + When the mass concentration is 7.0%-11.4%, the reaction effect is better.
[0181] Examples 26-28
[0182] Weigh the intermediate of the compound of formula II (9.8 g, 0.096 moL), the intermediate of the compound of formula I (23.8 g, 0.096 mol) and chlorobenzene (80 g) into a 250 mL three-necked flask, start heating, maintain the reaction temperature at 126 ° C, stir for 5 hours, stop the reaction, HPLC detection relative content is 98%, cool to room temperature (25 ° C), add 10 wt% hydrochloric acid aqueous solution (70 g, 0.192 mol) for extraction, phase separation, collect the organic phase, add potassium hydroxide aqueous solution to the organic phase at one time, add phase transfer catalyst tetrabutylammonium chloride (0.2668 g, 0.00096 mol), add or not add potassium chloride, cool to 0 ° C, slowly add pivaloyl chloride (11.52 g, 0.096 mol), after the addition is complete, stir for 10 minutes, take samples for analysis and detect the HPLC relative content. The organic phase was collected by phase separation, washed with water, concentrated to remove the organic solvent chlorobenzene, added with n-hexane (100 g) for crystallization, and filtered to obtain the product (the product was white).
[0183] The concentration of potassium hydroxide aqueous solution and the amount of potassium chloride were adjusted. The specific conditions and results are listed in Table 4:
[0184] Table 4
[0185]
[0186] Conclusion: From the results of the examples in Table 4, it can be seen that K + When the mass concentration is between 13.9% and 20.8%, the reaction conversion rate and total yield are relatively high.
[0187] Embodiment 29
[0188] Weigh the compound of formula II (9.8 g, 0.096 mol), the compound of formula I (23.8 g, 0.096 mol) and chlorobenzene (80 g) into a 250 mL three-necked flask, start heating, maintain the reaction temperature at 126°C, stir the reaction for 5 h, stop the reaction, and the relative content is 98% by HPLC. Cool to room temperature (25°C), add 10 wt% aqueous sodium hydroxide solution (46.08 g, 0.1152 mol) and tetrabutylammonium chloride (0.2668 g, 0.00096 mol), maintain the internal temperature below 10°C, slowly add pivaloyl chloride (11.52 g, 0.096 mol) dropwise, maintain the internal temperature at 10°C, stir for 10 min, take the organic phase for analysis, take samples for analysis, and the relative content by HPLC is 68%, and 30% of the raw materials are not completely reacted. Pivaloyl chloride (2.3 g, 0.0192 mol) was added, and the organic phase was analyzed. The relative content of HPLC was 71% after sampling and analysis, and 26% of the raw materials were unreacted. The phases were completely allowed to stand and separated, and the organic phase was collected. The organic phase was washed with 50 g of water, separated, and concentrated to remove chlorobenzene. N-hexane (100 g) was added for crystallization, and the product was filtered (the product HPLC purity was 96%, and the total yield was 69%).
[0189] Embodiment 30
[0190] Weigh the compound of formula II (9.8 g, 0.096 mol), the compound of formula I (23.8 g, 0.096 mol) and chlorobenzene (80 g) into a 250 mL three-necked flask, start heating, maintain the reaction temperature at 126°C, stir the reaction for 5 h, stop the reaction, and the relative content detected by HPLC is 98%. Cool to room temperature (25°C), add 20 wt% aqueous sodium hydroxide solution (23 g, 0.1152 mol) and tetrabutylammonium chloride (0.2668 g, 0.00096 mol), maintain the internal temperature below 10°C, slowly add pivaloyl chloride (11.52 g, 0.096 mol) dropwise, maintain the internal temperature at 10°C, stir for 10 min, take the organic phase for analysis, take samples for analysis, and the relative content detected by HPLC is 94%, and 4% of the raw materials are not completely reacted. Pivaloyl chloride (2.3 g, 0.0192 mol) was added, and the organic phase was analyzed. The relative content of HPLC was 98% after sampling and analysis. The raw materials were reacted completely. The phases were allowed to stand completely and separated. The organic phase was collected and washed with 50 g of water. The phases were separated and concentrated to remove chlorobenzene. N-hexane (100 g) was added for crystallization and the product was filtered (the product HPLC purity was 98.1% and the total yield was 94.5%).
Claims
1. A process for preparing pinoxaden improved, comprising the following steps: (1) Deamination reaction: reacting the compound of formula I with the compound of formula II in the presence of an organic solvent A that is immiscible with water to obtain a solution containing the compound of formula III; (2) an intermediate treatment step: contacting the solution containing the compound of formula III obtained in step (1) with an aqueous solution of an inorganic base to obtain a two-phase mixture; (3) Acylation reaction: reacting the two-phase mixture obtained in step (2) with pivaloyl chloride under sufficient mixing, and performing post-treatment to obtain pinoxaden; Wherein, the inorganic base in step (2) is sodium hydroxide, potassium hydroxide or lithium hydroxide; The mass concentration of alkali metal ions in the aqueous phase of the two-phase mixture in step (2) is 7%-30%.
2. The improved process for preparing pinoxaden according to claim 1, characterized in that: The inorganic base in step (2) is sodium hydroxide or potassium hydroxide.
3. The improved process for preparing pinoxaden according to claim 1, characterized in that: In step (2), a halide salt is added to the two-phase mixture; The halide salt is sodium chloride, potassium chloride, lithium chloride, sodium bromide, potassium bromide or lithium bromide.
4. The improved process for preparing pinoxaden according to claim 3, characterized in that: The halide salt is sodium chloride or potassium chloride.
5. The improved process for preparing pinoxaden according to any one of claims 1 to 4, characterized in that: The water-immiscible organic solvent A in step (1) is chlorobenzene, xylene or dichlorobenzene.
6. The improved process for preparing pinoxaden according to claim 5, characterized in that: The water-immiscible organic solvent A in step (1) is chlorobenzene.
7. The improved process for preparing pinoxaden according to any one of claims 1 to 4, characterized in that: In step (2), the solution containing the compound of formula III obtained in step (1) is contacted with an aqueous solution of an inorganic base, extracted and separated, and the aqueous phase is contacted with an organic solvent B that is immiscible with water to obtain a two-phase mixture.
8. The improved process for preparing pinoxaden according to claim 7, characterized in that: The water-immiscible organic solvent B in step (2) is 1,2-dichloroethane, dichloromethane, ethyl acetate or sec-butyl acetate.
9. The improved process for preparing pinoxaden according to claim 8, characterized in that: The water-immiscible organic solvent B in step (2) is 1,2-dichloroethane or ethyl acetate.
10. The improved process for preparing pinoxaden according to claim 9, characterized in that: The water-immiscible organic solvent B in step (2) is 1,2-dichloroethane.
11. The improved process for preparing pinoxaden according to any one of claims 1 to 4, characterized in that: In step (2), a phase transfer catalyst is added to the two-phase mixture; The phase transfer catalyst is a quaternary ammonium salt or a crown ether; The molar ratio of the phase transfer catalyst to the compound of formula I is 0.001-0.02:
1.
12. The improved process for preparing pinoxaden according to claim 11, characterized in that: The phase transfer catalyst is tetrabutylammonium chloride, tetramethylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium hydrogen sulfate or benzyltriethylammonium chloride.
13. The improved process for preparing pinoxaden according to claim 12, characterized in that: The phase transfer catalyst is tetrabutylammonium chloride or tetramethylammonium chloride.
14. The improved process for preparing pinoxaden according to claim 11, characterized in that: The molar ratio of the phase transfer catalyst to the compound of formula I is 0.01:
1.
15. The improved process for preparing pinoxaden according to any one of claims 1 to 4, characterized in that: In step (2), before the solution containing the compound of formula III obtained in step (1) is contacted with an aqueous solution of an inorganic base, the solution containing the compound of formula III is first contacted with an aqueous solution of an acid, extracted and separated, and then the organic phase is contacted with the aqueous solution of the inorganic base.
16. The improved process for preparing pinoxaden according to claim 15, characterized in that: The acid in step (2) is an inorganic acid or an organic acid; The mass concentration of the aqueous solution of the acid in step (2) is 2wt%-20wt%; The molar ratio of the acid to the compound of formula I in step (2) is 0.2-5:
1.
17. The improved process for preparing pinoxaden according to claim 16, characterized in that: The acid in step (2) is hydrochloric acid, sulfuric acid or acetic acid.
18. The improved process for preparing pinoxaden according to claim 17, characterized in that: The acid in step (2) is hydrochloric acid.
19. The improved process for preparing pinoxaden according to claim 16, characterized in that: The mass concentration of the aqueous solution of the acid in step (2) is 10wt%.
20. The improved process for preparing pinoxaden according to claim 16, characterized in that: The molar ratio of the acid to the compound of formula I in step (2) is 2:
1.
21. The improved process for preparing pinoxaden according to any one of claims 1 to 4, characterized in that: In step (1), the molar ratio of the compound of formula II to the compound of formula I is 1-5:1; The mass ratio of the water-immiscible organic solvent A to the compound of formula I in step (1) is 1-10:1; The reaction temperature in step (1) is 100°C-140°C; The molar ratio of pivaloyl chloride to the compound of formula I in step (3) is 1-3:1; The temperature of the reaction in step (3) is controlled at 0°C-25°C.
22. The improved process for preparing pinoxaden according to claim 21, characterized in that: The molar ratio of the compound of formula II to the compound of formula I in step (1) is 1:
1.
23. The improved process for preparing pinoxaden according to claim 21, characterized in that: The mass ratio of the water-immiscible organic solvent A to the compound of formula I in step (1) is 3-4:
1.
24. The improved process for preparing pinoxaden according to claim 21, characterized in that: The molar ratio of pivaloyl chloride to the compound of formula I in step (3) is 1:
1.
25. The improved process for preparing pinoxaden according to claim 21, characterized in that: In step (3), the temperature is controlled during the reaction, and the temperature of the temperature control is 0°C-20°C.
26. The improved process for preparing pinoxaden according to claim 25, characterized in that: In step (3), the temperature is controlled during the reaction, and the temperature of the temperature control is 0°C-10°C.